EP3481818B1 - Nouveaux procédés de préparation de stimulateurs de la guanylate cyclase soluble - Google Patents

Nouveaux procédés de préparation de stimulateurs de la guanylate cyclase soluble Download PDF

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EP3481818B1
EP3481818B1 EP17745553.2A EP17745553A EP3481818B1 EP 3481818 B1 EP3481818 B1 EP 3481818B1 EP 17745553 A EP17745553 A EP 17745553A EP 3481818 B1 EP3481818 B1 EP 3481818B1
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appropriate amount
formula
suitable temperature
organic solvent
compound
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EP3481818A1 (fr
EP3481818C0 (fr
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Song Xue
Vishnu Vardhan Reddy Karnati
Robert C. Livingston
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Cyclerion Therapeutics Inc
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Cyclerion Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates to novel processes for the preparation of compounds useful as stimulators of soluble guanylate cyclase (sGC). These processes are amenable to large scale preparation and produce stable 3-(2-pyrimidinyl)pyrazoles of Formula I in high purity and yields.
  • the present invention has the additional advantage of involving facile reaction conditions that are amenable to scale up for large scale manufacturing.
  • the disclosure also provides novel intermediates useful in the preparation of said compounds.
  • Compounds of Formula I and their pharmaceutically acceptable salts are sGC stimulators useful for treating diseases or disorders that benefit from sGC stimulation or from an increase in the concentration of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP).
  • Compounds of Formula I are also useful intermediates in the preparation of other sGC stimulators, including other compounds of Formula I.
  • sGC is the primary receptor for NO in vivo.
  • sGC can be activated via both NO-dependent and NO-independent mechanisms.
  • sGC converts guanosine-5'-triphosphate (GTP) into the secondary messenger cGMP.
  • GTP guanosine-5'-triphosphate
  • the increased level of cGMP in turn, modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs) and ion channels.
  • NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by sequential reduction of inorganic nitrate.
  • NOS nitric oxide synthase
  • Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle relaxation and blood pressure.
  • iNOS or NOS II inducible NOS
  • nNOS or NOS I constitutive neuronal NOS
  • eNOS or NOS III constitutive endothelial NOS
  • NO-independent, heme-dependent sGC stimulators displayed several important differentiating characteristics when compared with NO-independent, heme-independent sGC activators. These include crucial dependency on the presence of the reduced prosthetic heme moiety for their activity, strong synergistic enzyme activation when combined with NO and stimulation of the synthesis of cGMP by direct stimulation of sGC, independent of NO.
  • the benzylindazole compound YC-1 was the first sGC stimulator to be identified. Additional sGC stimulators with improved potency and specificity for sGC have since been developed.
  • WO 2015/089182 , WO 2014/144100 , WO 2013/101830 and WO2016044447 disclose compounds which are useful as stimulators of sGC.
  • WO 2017/095697 discloses solid dispersions of amorphous 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidi n-4-yl)amino)methyl)propan-2-ol, which is an sGC stimulator.
  • Some compounds of Formula I and their pharmaceutically acceptable salts are sGC stimulators that are useful for treating diseases or disorders that benefit from sGC stimulation or from an increase in the concentration of NO and/or cGMP.
  • Other compounds of Formula I are useful as intermediates in the synthesis of other sGC stimulators, including other compounds of Formula I.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound is one that is not substantially altered when kept at a temperature of 25°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • a chemically feasible compound is a compound that can be prepared by a person skilled in the art based on the disclosures herein supplemented, if necessary, with relevant knowledge of the art.
  • a compound such as the compounds of Formula I or other compounds herein disclosed, may be present in its free form (e.g. an amorphous form, or a crystalline form or a polymorph). Under certain conditions, compounds may also form co-forms. As used herein, the term co-form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred or lost a proton, the resulting co-form is referred to as a "salt". The formation of a salt is determined by how large the difference is in the pKas between the partners that form the mixture.
  • the term “compound” also includes a pharmaceutically acceptable salt of the compound, whether or not the phrase “pharmaceutically acceptable salt” is actually used.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
  • the pharmaceutically acceptable salts of a compound described herein are used in medicine. Salts that are not pharmaceutically acceptable may, however, be useful in the preparation of a compound described herein or of other pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt involves the inclusion of another atom or molecule acting as the counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. In some instances, the counter ions may be the same. In other instances, they may be different for each charged atom. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ions.
  • salts of the compounds described herein include those derived from the reaction of the compounds described herein with inorganic or organic bases.
  • the salts can be prepared in situ during the final isolation and purification of the compounds.
  • the salts can be prepared from the free form of the compound described herein in a separate synthetic step.
  • structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure; for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure.
  • stereoisomeric e.g., enantiomeric, diastereomeric, atropoisomeric and cis-trans isomeric
  • the present disclosure also embraces isotopically-labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • each instance of that substituent is chosen independently in each instance. For example, if a phenyl can be substituted with two instances of R 100 , and R 100 is selected from halogen and methyl, then that means that each instance of R 100 is separately selected from halogen or methyl; for instance, one R 100 may be fluoro and one may be methyl, or both may be chloro, etc.
  • a group may be substituted with "up to" Z instances of a substituent, wherein "Z” is an integer. For instance, if “Z” is 3, then the group can be substituted with 0, 1, 2, or 3 substituents. Unless otherwise specified, each of those "Z" instances are always independently selected .
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical.
  • a C x alkyl is an alkyl chain containing x carbon atoms, wherein x is an integer different from 0.
  • a "C x-y alkyl”, wherein x and y are two different integers, both different from 0, is an alkyl chain containing between x and y number of carbon atoms, inclusive.
  • a C 1-6 alkyl is an alkyl as defined above containing any number between 1 and 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (C 1 alkyl), ethyl (C 2 alkyl), n-propyl (C 3 alkyl), isopropyl C 3 alkyl), n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • aryl refers to a carbocyclic ring system that is aromatic and has a single point of attachment to the rest of the molecule.
  • An example of an aryl ring is phenyl.
  • heteroaryl refers to a ring system that is aromatic and contains one or more heteroatoms, which has a single point of attachment to the rest of the molecule.
  • a heteroaryl ring is a 5 to 6-membered heteroaryl ring. In other embodiments, it is a 5-membered heteroaryl ring. In still other embodiments, it is a 6-membered heteroaryl ring.
  • heteroaryl rings include, but are not limited to the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-
  • ring atom refers to an atom such as C, N, O or S that is part of the ring of a phenyl or a heteroaryl ring.
  • a “substitutable ring atom” is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. "Substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution. When a certain ring, group or chain is optionally substituted, it will be understood that it may be substituted in any or some or all of its substitutable ring atoms.
  • Heteroatom refers to one or more of oxygen, sulfur or nitrogen including any oxidized form of nitrogen or sulfur the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • halogen or halo means F, Cl, Br, or I.
  • haloalkyl means alkyl substituted with one or more halogen atoms.
  • a C 1-3 haloalkyl could be -CFHCH 2 CHF 2 .
  • fluoroalkyl means alkyl substituted with one or more fluorine atoms. This term includes perfluorinated alkyl groups, such as -CF 3 and -CF 2 CF 3 .
  • alkoxy refers to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen atom. "Alkoxy” can be described as -O-C x-y alkyl or C x-y alkoxy.
  • hydroxyl or "hydroxy” refers to -OH.
  • solvent refers to an individual solvent or to a mixture of solvents that result in the desired properties of the solvent mixture.
  • an "aprotic organic solvent” or “an aprotic solvent”, as defined below could be toluene, or it could be a mixture of toluene and another aprotic solvent such as DMF.
  • aprotic organic solvent or aprotic solvent could also encompass a toluene/DMF mixture as long as the resulting properties of the mixture are those of an aprotic solvent.
  • a protic solvent as defined below, could encompass water or a mixture of water and methanol.
  • a protic solvent is a solvent that has a hydrogen atom bound to a polar group, such as oxygen (as in a hydroxyl group) or nitrogen (as in an amine group).
  • a protic solvent any solvent that contains labile H+ is called a protic solvent.
  • the molecules of such solvents readily donate protons (H+) to reagents.
  • protic solvents cannot easily donate hydrogen.
  • Protic solvents are usually polar solvents as they have high dielectric constants and high polarity.
  • Aprotic solvents are usually classified as either polar aprotic or non-polar (or apolar) aprotic depending on the values of their dielectric constants.
  • aprotic solvent and “aprotic organic solvent” are used interchangeably.
  • protic solvents Some common characteristics of protic solvents are the ability to display hydrogen bonding, having acidic hydrogens (although they may be very weakly acidic, such as ethanol) and that they are able to dissolve salts.
  • acidic hydrogens although they may be very weakly acidic, such as ethanol
  • Non-limiting examples include water, most alcohols (e.g., methanol, ethanol, propanol, butanol, isopropanol, isobutanol, etc.), formic acid, hydrogen fluoride, nitromethane, acetic acid and ammonia.
  • aprotic solvents Some common characteristics of aprotic solvents are that they can accept hydrogen bonds, do not have acidic hydrogen and are, only sometimes, able to dissolve salts. These criteria are relative and very qualitative. A range of acidities are recognized for aprotic solvents. Their ability to dissolve salts depends strongly on the nature of the salt.
  • Polar aprotic solvents usually can dissolve salts. They lack an acidic hydrogen. Consequently, they are not hydrogen bond donors. These solvents generally have intermediate dielectric constants and polarity. Although it discourages the use of the term "polar aprotic", IUPAC describes such solvents as having both high dielectric constants and high dipole moments, an example being acetonitrile.
  • solvents meeting IUPAC's criteria include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), hexamethylphosphoramide (HMPA), tetrahydrofuran, ethyl acetate, acetone, acetonitrile (MeCN), and dimethylsulfoxide (DMSO).
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • NMP N-methylpyrrolidone
  • HMPA hexamethylphosphoramide
  • tetrahydrofuran ethyl acetate
  • MeCN acetonitrile
  • DMSO dimethylsulfoxide
  • Apolar or non-polar aprotic solvents usually have small dielectric constants.
  • Some examples of apolar or non-polar aprotic (organic) solvents are hexane, pentane, decane and other alkanes, benzene, toluene, 1, 4-dioxane, chloroform, ethers such as diethyl ether, dichloromethane, dichloroethane, etc.
  • equivalent when discussing an amount of a reagent used, refers to "molar equivalent".
  • one equivalent of reagent A for each equivalent of reagent B means one mole of reagent A for each mole of reagent B is used in the reaction.
  • a mole is defined as the number that results when the total weight of a substance used is divided by the molecular weight of said substance, both weights being in the same units (for example, grams).
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • Some compounds of Formula I and their pharmaceutically acceptable salts are sGC stimulators that are useful for treating diseases or disorders that benefit from sGC stimulation or from an increase in the concentration of NO and/or cGMP).
  • Other compounds of Formula I are useful as intermediates in the synthesis of other sGC stimulators, including other compounds of Formula I.
  • a compound of Formula I the following definitions apply:
  • One aspect of the invention provides a process for making a compound of Formula II, depicted below, said process comprising the steps of:
  • Also disclosed is an alternative one-step process for the synthesis of a compound of Formula II comprising the direct selective de-chlorination of dichloropyrimidine (7) with hydrogen gas or a transfer hydrogenation reagent and, optionally, an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in a suitable organic solvent, to provide mono-chloropyrimidine of Formula II.
  • R 1 is an unsubstituted 5-membered heteroaryl ring, containing up to 3 heteroatoms independently selected from N, O or S.
  • R 1 is isoxazolyl.
  • R 1 is 3-isoxazolyl.
  • R 1 is unsubstituted phenyl or 6-membered heteroaryl ring containing up to three ring nitrogen atoms.
  • R 1 is a pyridine or pyrimidine.
  • R 1 is phenyl.
  • R 2 is a 6-membered heteroaryl optionally substituted with up to three instances of R 5 .
  • R 2 is phenyl optionally substituted with up to three instances of R 5 .
  • R 2 is phenyl substituted with one instance of R 5 .
  • R 2 is phenyl substituted with one instance of R 5 and R 5 is halogen.
  • R 2 is phenyl substituted with one instance of R 5 and R 5 is fluoro. In other embodiments, R 2 is 2-fluorophenyl. In yet other embodiments, R 2 is phenyl substituted with two instances of R 5 . In yet other embodiments, R 2 is phenyl substituted with two instances of R 5 and each instance of R 5 is independently selected from halogen. In still other embodiments, R 2 is phenyl substituted with two instances of R 5 and each instance of R 5 is fluoro.
  • the one-step process for making a compound of Formula III comprises the step of coupling an appropriate amount of an amine (13) with a chloropyrimidine of Formula II, in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, at a suitable temperature, to yield a compound of Formula III.
  • R 1 may be an unsubstituted 5-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S.
  • R 1 may be isoxazolyl.
  • R 1 may be 3-isoxazolyl.
  • R 1 may be an unsubstituted phenyl or 6-membered heteroaryl containing up to three ring nitrogen atoms.
  • R 1 may be pyrimidine.
  • R 1 may be pyridine.
  • R 1 may be phenyl.
  • R 2 may be a 6-membered heteroaryl optionally substituted with up to three instances of R 5 .
  • R 2 may be phenyl optionally substituted with up to three instances of R 5 .
  • R 2 may be phenyl substituted with one instance of R 5 .
  • R 2 may be phenyl substituted with one instance of R 5 and R 5 is halogen.
  • R 2 may be phenyl substituted with one instance of R 5 and R 5 is fluoro.
  • R 2 may be 2-fluorophenyl.
  • R 2 may be phenyl substituted with two instances of R 5 .
  • R 2 may be phenyl substituted with two instances of R 5 and each instance of R 5 may be independently selected from halogen.
  • R 2 may be phenyl substituted with two instances of R 5 and each instance of R 5 may be fluoro.
  • R 6 may be hydrogen, methyl or ethyl in intermediate (13), in the compound of Formula III and in the intermediate of Formula VII.
  • R 6 may be hydrogen in intermediate (13), in the compound of Formula III and in the intermediate of Formula VII.
  • R 7 may be C 1-6 alkyl in intermediate (13) and the compound of Formula III and intermediate of Formula VII, and the C 1-6 alkyl may be substituted with up to 3 instances of R 8 .
  • R 7 may be C 1-2 alkyl substituted with up to 3 instances of R 8 .
  • R 7 may be ethyl, substituted with 3 instances of R 8 .
  • one instance of R 8 may be -OH.
  • One instance of R 8 may be -OH and the other two instances may independently be C 1-3 haloalkyl.
  • One instance of R 8 is -OH and the other two instances may be trifluoromethyl.
  • R 7 may be ethyl in intermediate (13), intermediate of Formula VII and the compound of Formula III, the; ethyl may be substituted with 3 instances of R 8 , and one of the three instances of R 8 may be -OH.
  • R 7 may be ethyl substituted with 3 instances of R 8 , and one of the instances of R 8 may be -OH and the other two instances of R 8 may independently be C 1-3 haloalkyl.
  • one instance of R 8 may be -OH and the other two instances of R 8 may be trifluoromethyl.
  • Also disclosed herein is an alternative one-step process for the synthesis of a compound of Formula IV comprising the direct selective de-chlorinating of dichloropyrimidine (7') with hydrogen gas or a transfer hydrogenation reagent and, optionally, an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in a suitable organic solvent, to provide the mono-chloropyrimidine of Formula IV.
  • a suitable equivalent reagent to oxalyl chloride is, for instance thionyl chloride or 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC).
  • An appropriate amount of oxalyl chloride or equivalent reagent is at least one equivalent of oxalyl chloride per equivalent of starting material (1) or starting material (1'). In some embodiments, an appropriate amount is between about 1 and about 3 equivalents. In other embodiments, an appropriate amount is between about 1 and about 2 equivalents. In still other embodiments, an appropriate amount is between about 1 and about 1.5 equivalents. In yet other embodiments, an appropriate amount is between about 1.1 and about 1.3 equivalents. In yet other embodiments, an appropriate amount is about 1.1 equivalents or about 1.2 equivalents.
  • a suitable aprotic organic solvent is, for instance toluene.
  • Other suitable solvents are, for example, methylene chloride or tetrahydrofuran.
  • a suitable catalyst is DMF.
  • An appropriate amount of DMF is a catalytic amount, i.e., less than one equivalent of DMF per each equivalent of starting material (1) or starting material (1'). In some embodiments, an appropriate amount is between about 0.01 and about 0.09 equivalents. In other embodiments, it is between about 0.01 and about 0.07 equivalents. In still other embodiments, it is between about 0.02 and about 0.07 equivalents. In still other embodiments it is between about 0.04 and about 0.06 equivalents.
  • a suitable temperature for the reaction of starting material (1) or starting material (1') with oxalyl chloride or thionyl chloride is a temperature between about 45 °C and about 60 °C. In some embodiments, a suitable temperature is between about 45 °C and about 50 °C. In other embodiments, it is a temperature of about 50 °C.
  • a suitable temperature for the reaction of starting material (1) or starting material (1') with EDAC is a temperature between about -10 °C and about 25 °C. In some embodiments, a suitable temperature is between about -10 °C and about 20 °C. In some embodiments, a suitable temperature is between about -10 °C and about 0 °C. In some embodiments, a suitable temperature is between about -10 °C and about -5 °C.
  • An appropriate amount of N,O-dimethylhydroxylamine hydrochloride is at least one equivalent of N,O-dimethylhydroxylamine hydrochloride per each equivalent of starting material (1) or starting material (1'). In other embodiments, an appropriate amount of N,O-dimethylhydroxylamine hydrochloride is between about 1 equivalent and about 2 equivalents per each equivalent of starting material (1) or starting material (1'). In other embodiments, it is between about 1 equivalent and about 1.5 equivalents. In other embodiments, it is between about 1 equivalent and about 1.2 equivalents. In other embodiments, it is between about 1.1 equivalents and about 1.2 equivalents.
  • a suitable base is, for instance, K 2 CO 3 or NaOH.
  • Other suitable inorganic bases are, for example, NaHCO 3 , KHCO 3 , Et 3 N, or Hunig's base.
  • An appropriate excess of said suitable base is at least 1.1 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride used. In some embodiments, an appropriate amount is between about 1.1 and about 5 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride. In some embodiments, an appropriate amount is between about 1.2 and about 5 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride. In other embodiments, it is about 2 to about 3 equivalents. In still other embodiments, it is between about 2 and about 4 equivalents. In other embodiments, it is about 1.2 to about 3 equivalents. In other embodiments, it is about 1.2 to about 3 equivalents. In other embodiments, it is about 1.5 to about 3 equivalents. In other embodiments, it is about 1.2 to about 4 equivalents. In still other embodiments, it is between about 1.5 and about 4 equivalents. In other embodiments, it is about 1.2 to about 2 equivalents.
  • a suitable temperature for the reaction of N,O-dimethylhydroxylamine hydrochloride and the suitable base is a temperature between about -10 °C and about 25 °C. In some embodiments, a suitable temperature is between about -10 °C and about 20 °C. In some embodiments, a suitable temperature is between about -10 °C and about 0 °C. In some embodiments, a suitable temperature is between about -10 °C and about -5 °C.
  • a suitable solvent for the water/aprotic solvent mixture is, for instance, dichloromethane (DCM).
  • DCM dichloromethane
  • Other suitable solvents are, for example, ethyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran.
  • an appropriate amount of ethyl propiolate is at least one equivalent of ethyl propiolate per equivalent of intermediate (2) or intermediate (2').
  • an appropriate amount of ethyl propiolate is between about 1 and about 2 equivalents. In other embodiments, it is between about 1 and about 1.8 equivalents. In other embodiments, it is between about 1 and about 1.6 equivalents. In still other embodiments, it is between about 1.1 and about 1.5 equivalents. In yet other embodiments, it is about 1.1 equivalents. In still other embodiments, it is about 1.5 equivalents.
  • a suitable aprotic organic solvent is an anhydrous organic solvent.
  • a suitable solvent is anhydrous tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • Other suitable solvents in this step are, for example, 2-methyltetrahydrofuran and toluene.
  • a suitable temperature is a temperature of about -75 °C to about -30 °C. In some embodiments, a suitable temperature is one between about -70 °C to about -50 °C. In some embodiments, a suitable temperature is between about -65 °C to about -50 °C. In other embodiments, a suitable temperature is between about -65 °C to about -55 °C. In still other embodiments, a suitable temperature is between about -70 °C to about -60 °C.
  • a suitable base is, for instance, sodium bis(trimethylsilyl)amide (NaHMDS).
  • Other suitable bases are, for instance, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and lithium diisopropylamide.
  • An appropriate amount of a suitable base is between about 1 equivalent and about 1.65 equivalents per each equivalent of intermediate (2) or intermediate (2'). In some embodiments, it is between about 1 equivalent and about 1.5 equivalents. In some embodiments, it is between about 1 equivalent and about 1.3 equivalents. In other embodiments, it is between about 1.1 equivalents and about 1.65 equivalents. In other embodiments, it is between about 1.1 equivalents and about 1.5 equivalents. In still other embodiments, it is between about 1.1 equivalents and about 1.4 equivalents. In yet other embodiments it is between 1.1 equivalents and about 1.3 equivalents.
  • an appropriate amount of hydrazine is at least one equivalent of hydrazine per each equivalent of intermediate (3) or intermediate (3'). In some embodiments, an appropriate amount of hydrazine is between about 1 equivalent and about 2 equivalents. In other embodiments, it is between about 1 equivalent and about 1.5 equivalent. In still other embodiments, it is between about 1 equivalent and about 1.3 equivalents. In still other embodiments, it is between about 1.1 equivalents and about 1.4 equivalents. In still other embodiments it is between 1.1 equivalents and about 1.3 equivalents.
  • An optional suitable base is, for instance, potassium carbonate (K 2 CO 3 ).
  • Other optional suitable organic bases in this step are, for example, sodium acetate (NaOAc), sodium carbonate (Na 2 CO 3 ), sodium hydrogen carbonate (NaHCO 3 ) and potassium bicarbonate (KHCO 3 ).
  • An appropriate amount of a suitable base is an amount that will neutralize the acid from the hydrazine hydrochloride, when the hydrochloride form of the hydrazine is used. For instance, about 0.5 to about 1.1 equivalents of base per each equivalent of hydrazine hydrochloride. In other embodiments, an appropriate amount is about 0.5 to about 0.9 equivalents. In still other embodiments, it is about 0.65 equivalents.
  • a suitable protic solvent is, for instance, absolute ethanol or isopropanol.
  • Other solvents that may be used in this step are, for example dichloromethane, isopropanol and methanol.
  • a suitable temperature is between about 0 °C and about 40 °C. In other embodiments, a suitable temperature is between about 0 °C and about 30 °C. In some embodiments, it is between about 0 °C and about 25 °C. In other embodiments, it is between about 0 °C and about 15 °C. In other embodiments, it is between about 0 °C and about 10 °C. In still other embodiments, it is between about 10 °C and about 25 °C.
  • An appropriate amount of ammonium chloride is between about 2.5 and about 6 equivalents of ammonium chloride for each equivalent of intermediate (4) or intermediate (4'). In some embodiments, an appropriate amount is between about 2.5 and about 5.5 equivalents. In some embodiments, an appropriate amount is between about 3.5 and about 4 equivalents. In other embodiments, an appropriate amount is about 3.8 equivalents. In still other embodiments, an appropriate amount is about 3.5 equivalents. In some embodiments, an appropriate amount is between about 4.5 equivalents and 5.0 equivalents. In other embodiments, an appropriate amount is about 4.8 equivalents.
  • An appropriate amount of trimethylaluminum is between about 2.5 and about 5.5 equivalents of trimethylaluminum for each equivalent of intermediate (4) or intermediate (4'). In some embodiments, an appropriate amount is between about 3.5 and about 5.5 equivalents. In other embodiments, an appropriate amount is between about 3.5 and about 4.5 equivalents. In other embodiments, an appropriate amount is between about 3.5 and about 4 equivalents. In other embodiments, an appropriate amount is about 3.5 equivalents.
  • a suitable aprotic organic solvent is, for instance, toluene.
  • Other suitable solvents are, for example, xylene.
  • a suitable temperature for toluene is between about 60 °C and about 115 °C. In some embodiments, a suitable temperature is between about 70 °C and about 110 °C. In other embodiments, it is between about 70 °C and about 110 °C. In still other embodiments, it is between about between about 80 °C and about 110 °C. In still other embodiments, it is between about 90 °C and about 110 °C.
  • a suitable temperature for xylene is between about 70 °C and about 130 °C.
  • a suitable aqueous mineral acid is concentrated HCl, for instance 3 N HCl or 37 % by weight HCl.
  • Other suitable mineral acids that can be used to induce the precipitation of the intermediate (4) or intermediate (4') are, for instance, H 2 SO 4 .
  • An appropriate amount of fluoromalonate is at least one equivalent of fluoromalonate per each equivalent of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In some embodiments, it is between about 1 equivalent and about 2 equivalents of fluoromalonate. In still other embodiments, it is between about 1.2 equivalents and about 2 equivalents. In still other embodiments, it is between about 1.3 and about 1.9 equivalents. In other embodiments, it is between 1.4 and 1.6 equivalents. In other embodiments, it is between about 1.7 and 1.9 equivalents.
  • a suitable base is, for instance, sodium methoxide (NaOMe).
  • NaOMe sodium methoxide
  • MeOH a solution in MeOH.
  • a 23 % wt solution in MeOH can be used.
  • 30 % wt solution in MeOH can be used.
  • a 5.4 M solution in MeOH could be used.
  • Other bases that could be used in this step include EtONa.
  • An appropriate amount of a suitable base is an excess with respect to the amount of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In some embodiments, an appropriate amount is between about 3 and about 10 equivalents of NaOMe per each equivalent of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In other embodiments, an appropriate amount is between about 3 and about 6 equivalents. In still other embodiments, it is between about 3 and about 5 equivalents. In still other embodiments, it is between about 4 and about 5 equivalents. In yet other embodiments, an appropriate amount is about 4.5 equivalents.
  • a suitable protic solvent is, for example, MeOH.
  • Other suitable solvents that could be used in this step include EtOH.
  • a suitable temperature is between about 10 °C and about 40 °C. In some embodiments, a suitable temperature is between about 15 °C and about 35 °C. In other embodiments, a suitable temperature is between about 15 °C and about 30 °C. In other embodiments, a suitable temperature is between about 20 °C and about 35 °C. In still other embodiments, a suitable temperature is between about 20 °C and about 30 °C.
  • a suitable mineral acid is, for example, 1.5 N HCl.
  • Other suitable mineral acids that could be used in this step include sulfuric acid.
  • An appropriate amount of a mineral acid is at least an excess with respect to the amount of the suitable base used.
  • an appropriate amount is at least one equivalent of mineral acid per each equivalent of base used (e.g., NaOMe).
  • an appropriate amount is about 1.1 equivalents of mineral acid per each equivalent of base.
  • an appropriate amount of mineral acid is between about 4.5 and about 5.5 equivalents of mineral acid per each equivalent of intermediate (5B) or intermediate (5'B).
  • an appropriate amount of mineral acid is between about 4.7 and about 5.0 equivalents. In still other embodiments, it is about 4.9 equivalents.
  • An appropriate amount of POCl 3 is at least two equivalents of POCl 3 per each equivalent of intermediate (6) or intermediate (6') used. In some embodiments, an appropriate amount of POCl 3 is at least 4 equivalents. In some embodiments, an appropriate amount is at least 5 equivalents. In still other embodiments, an appropriate amount is about 6 equivalents of POCl 3 per each equivalent of intermediate (6) or intermediate (6').
  • a suitable temperature is between about 60 °C and about 90 °C. In some embodiments, a suitable temperature is between about 65 °C and about 90 °C. In other embodiments, a suitable temperature is between about 70 °C and about 90 °C. In still other embodiments, a suitable temperature is between about 75 °C and about 90 °C. In yet other embodiments, a suitable temperature is between about 70 °C and about 80 °C.
  • a suitable aprotic organic solvent is, for instance, acetonitrile (CNMe).
  • CCMe acetonitrile
  • a suitable optional base is, for instance, N,N -dimethylaniline.
  • the reaction also works in the absence of a base.
  • An appropriate amount of a suitable base is between about 0.2 and about 2 equivalents of base per each equivalent of intermediate (6) or intermediate (6') used. In some embodiments, an appropriate amount of base is between about 1.5 and about 1.8 equivalents. In other embodiments, it is between about 0.8 equivalents and about 1.2 equivalents. In still other embodiments, it is about 1 equivalent.
  • an appropriate amount of sodium methoxide is about 1 equivalent of NaOMe per each equivalent of intermediate (7) or intermediate (7').
  • an appropriate amount of NaOMe is a slight excess of NaOMe per each equivalent of intermediate (7) or intermediate (7').
  • an appropriate amount of NaOMe is between 1.1 and 1.3 equivalents per each equivalent of intermediate (7) or intermediate (7'). In other embodiments, an appropriate amount is about 1.2 equivalents.
  • a suitable temperature is between about 15 °C and about 30 °C. In some embodiments, a suitable temperature is between about 20 °C and about 30 °C. In other embodiments, it is between about 15 °C and about 28 °C. In other embodiments, between about 20 °C and about 28 °C. In still other embodiments, between about 23 °C and about 27 °C.
  • a suitable protic solvent is, for instance, methanol (MeOH).
  • a suitable transfer hydrogenation reagent is HCOOH.
  • HCOOH was most commonly used in the presence of organic/inorganic bases such as Et 3 N, NaOH, NaHCO 3 , etc.
  • a suitable metal catalyst is palladium on activated carbon, for instance 10 % Pd on activated carbon.
  • An appropriate amount of a suitable metal catalyst is a catalytic amount, i.e., less than one equivalent of Pd per equivalent of intermediate (8) or intermediate (8'). In some embodiments, an appropriate amount of the suitable metal catalyst is between 0.01 and 0.03 equivalents of Pd per equivalent of intermediate (8) or intermediate (8'). In other embodiments, an appropriate amount of the suitable metal catalyst is between 0.01 and 0.025 equivalents of Pd per equivalent of intermediate (8) or intermediate (8'). In still other embodiments, an appropriate amount of the suitable metal catalyst is between 0.015 and 0.025 equivalents of Pd per equivalent of intermediate (8) or intermediate (8'). In yet other embodiments, an appropriate amount of the suitable metal catalyst is between 0.01 and 0.02 equivalents of Pd per equivalent of intermediate (8) or intermediate (8').
  • a suitable base is triethylamine (Et 3 N).
  • Other suitable bases that can be used are, for example, Hunig's base, NaHCOs, KHCO 3 , and sodium acetate.
  • An appropriate amount of a suitable base is at least one equivalent of base per each equivalent of intermediate (8) or intermediate (8'). In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.
  • a suitable temperature is between about 35 °C and about 60 °C.
  • a suitable temperature is between about 35 °C and about 55 °C. In some embodiments, a suitable temperature is between about 40 °C and about 50 °C.
  • a suitable organic solvent is, for example, THF.
  • Other solvents that can be used are, for instance methanol, ethanol, isopropanol, 2-methyl-tetrahydrofuran or mixtures thereof.
  • a suitable aqueous acid is HCl.
  • Other acids that could be used include, for instance, methylsulfonic acid (MeSOsH) or HBr.
  • An appropriate amount of acid is between about 3 and about 6 equivalents. In some embodiments, an appropriate amount is between about 4 and about 6 equivalents. In other embodiments, it is between about 4.5 equivalents and about 6 equivalents. In still other embodiments, it is about 4.90 to about 5 equivalents.
  • HCl can be provided, for instance, in the form of concentrated HCl (e.g., 37 wt % HCl).
  • a suitable protic solvent is, for instance, MeOH.
  • Other suitable protic solvents are EtOH and iPrOH.
  • a suitable temperature is between about 50 °C and about 70 °C. In some embodiments, a suitable temperature is between about 55 °C and about 65 °C. In still other embodiments, a suitable temperature is between about 60 °C and about 65 °C. In still other embodiments, a suitable temperature is between about 62 °C and about 65 °C.
  • An appropriate amount of POCl 3 is at least two equivalents of POCl 3 per each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, an appropriate amount of POCl 3 is at least 4 equivalents. In some embodiments, an appropriate amount is at least 3 equivalents. In some embodiments, an appropriate amount is at least 2 equivalents. In some embodiments, an appropriate amount is at least 1 equivalent. In still other embodiments, an appropriate amount is between about 1 and about 4 equivalents of POCl 3 per each equivalent of intermediate (10) or intermediate (10').
  • a suitable temperature is between about 50 °C and about 90 °C. In some embodiments, a suitable temperature is between about 60 °C and about 90 °C. In some embodiments, a suitable temperature is between about 65 °C and about 90 °C. In other embodiments, a suitable temperature is between about 70 °C and about 90 °C. In still other embodiments, a suitable temperature is between about 75 °C and about 90 °C. In yet other embodiments, a suitable temperature is between about 75 °C and about 85 °C. In other embodiments, a suitable temperature is between about 75 °C and about 80 °C.
  • a suitable aprotic solvent is, for instance, acetonitrile (CNMe).
  • CCMe acetonitrile
  • a suitable optional base is, for instance, N,N -dimethylaniline.
  • the reaction also works in the absence of a base.
  • An appropriate amount of a suitable base is between about 0.2 and about 2 equivalents of base per each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, an appropriate amount of base is between about 1.3 and about 1.6 equivalents. In some embodiments, an appropriate amount of base is between about 1.2 and about 1.8 equivalents. In other embodiments, it is about 1 equivalent.
  • An appropriate amount of sodium hydroxide (NaOH) is between about 2 and about 2.5 equivalents of NaOH per each equivalent of intermediate (7) or intermediate (7'). In other embodiments, an appropriate amount is about 2.2 equivalents.
  • a suitable temperature is between about 45 °C and about 70 °C. In some embodiments, a suitable temperature is between about 50 °C and about 65 °C. In other embodiments, it is between about 55 °C and about 60 °C.
  • phase transfer catalyst is tetrabutylammonium hydroxide.
  • suitable phase transfer catalysts that could be used comprise benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride.
  • An appropriate amount of a suitable phase transfer catalyst is a catalytic amount, i.e., less than one equivalent of phase transfer catalyst per equivalent of intermediate (7) or intermediate (7').
  • a catalytic amount is between about 0.1 and about 0.5 equivalents. In other embodiments, it is between about 0.1 and about 2.5 equivalents. In still other embodiments, it is between about 0.1 and about 0.15 equivalents.
  • a suitable protic solvent is, for instance, water.
  • a suitable aprotic solvent is, for example, tetrahydrofuran.
  • a suitable transfer hydrogenation reagent is HCOOH.
  • HCOOH was most commonly used in the presence of organic/inorganic bases such as Et 3 N, NaOH, NaHCO 3 , etc.
  • a suitable metal catalyst is palladium on activated carbon, for instance 10 % Pd on activated carbon.
  • An appropriate amount of a suitable metal catalyst is a catalytic amount, i.e., less than one equivalent of Pd per equivalent of intermediate (8B) or intermediate (8'B). In some embodiments, an appropriate amount of the suitable metal catalyst is between 0.01 and 0.02 equivalents of Pd per equivalent of intermediate (8B) or intermediate (8'B).
  • a suitable base is triethylamine (Et 3 N).
  • Other suitable bases that can be used are, for example, Hunig's base, NaHCOs, KHCO 3 , and sodium acetate.
  • An appropriate amount of a suitable base is at least one equivalent of base per each equivalent of intermediate (8B) or intermediate (8'B). In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.
  • a suitable temperature is between about 15 °C and about 60 °C. In some embodiments, a suitable temperature is between about 15 °C and about 55 °C. In some embodiments, a suitable temperature is between about 35 °C and about 55 °C. In other embodiments, a suitable temperature is between about 40 °C and about 50 °C. In still other embodiments, a suitable temperature is between about 15 °C and about 25 °C. In yet other embodiments, a suitable temperature is between about 20 °C and about 30 °C. In still other embodiments, a suitable temperature is between about 20 °C and about 25 °C.
  • a suitable organic solvent is, for example, THF.
  • Other solvents that can be used are, for instance methanol, ethanol, isopropanol, 2-methyl-tetrahydrofuran or mixtures thereof.
  • An appropriate amount of POCl 3 is at least two equivalents of POCl 3 per each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, an appropriate amount of POCl 3 is at least 4 equivalents. In some embodiments, an appropriate amount is at least 3 equivalents. In some embodiments, an appropriate amount is at least 2 equivalents. In some embodiments, an appropriate amount is at least 1 equivalent. In still other embodiments, an appropriate amount is between about 1 and about 4 equivalents of POCl 3 per each equivalent of intermediate (10) or intermediate (10').
  • a suitable temperature is between about 50 °C and about 80 °C. In some embodiments, a suitable temperature is between about 60 °C and about 80 °C. In some embodiments, a suitable temperature is between about 65 °C and about 80 °C. In other embodiments, a suitable temperature is between about 70 °C and about 80 °C. In still other embodiments, a suitable temperature is between about 75 °C and about 80 °C.
  • a suitable aprotic solvent is, for instance, acetonitrile (CNMe).
  • CCMe acetonitrile
  • a suitable optional base is, for instance, N,N -dimethylaniline.
  • the reaction also works in the absence of a base.
  • An appropriate amount of a suitable base is between about 0.2 and about 2 equivalents of base per each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, an appropriate amount of base is between about 1.3 and about 1.6 equivalents. In some embodiments, an appropriate amount of base is between about 1.2 and about 1.8 equivalents. In other embodiments, it is about 1 equivalent.
  • a suitable transfer hydrogenation reagent is HCOOH.
  • HCOOH was most commonly used in the presence of organic/inorganic bases such as Et 3 N, NaOH, NaHCO 3 , etc.
  • a suitable metal catalyst is palladium on activated carbon, for instance 10 % Pd on activated carbon.
  • An appropriate amount of a suitable metal catalyst is a catalytic amount, i.e., less than one equivalent of Pd per equivalent of intermediate (7) or intermediate (7'). In some embodiments, an appropriate amount of the suitable metal catalyst is between 0.01 and 0.02 equivalents of Pd per equivalent of intermediate (7) or intermediate (7').
  • a suitable base is triethylamine (Et 3 N).
  • Other suitable bases that can be used are, for example, Hunig's base, NaHCOs, KHCO 3 , and sodium acetate.
  • An appropriate amount of a suitable base is at least one equivalent of base per each equivalent of intermediate (7) or intermediate (7'). In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.
  • a suitable temperature is between about 35 °C and about 60 °C.
  • a suitable temperature is between about 35 °C and about 55 °C. In some embodiments, a suitable temperature is between about 40 °C and about 50 °C.
  • a suitable organic solvent is, for example, THF.
  • Other solvents that can be used are, for instance methanol, ethanol, isopropanol, 2-methyl-tetrahydrofuran or mixtures thereof.
  • Also disclosed herein is a one-step process for making a compound of Formula V.
  • the one-step process for making a compound of Formula V comprises coupling an appropriate amount of an amine (13) with a chloropyrimidine of Formula IV, optionally in the presence of an appropriate amount of a suitable base, in a suitable aprotic organic solvent, at a suitable temperature, to yield a compound of Formula V.
  • R 6 may be hydrogen, methyl or ethyl in intermediate (13), the compound of Formula V and the intermediate of Formula VIII.
  • R 6 may be hydrogen in intermediate (13), the compound of Formula V and the intermediate of Formula VIII.
  • R 7 may be C 1-6 alkyl in intermediate (13), intermediate of Formula VIII and the compound of Formula V, and the C 1-6 alkyl may be substituted with up to 3 instances of R 8 .
  • R 7 may be C 1-2 alkyl, substituted with up to 3 instances of R 8 .
  • R 7 may be ethyl, substituted with 3 instances of R 8 .
  • one instance of R 8 may be -OH.
  • One instance of R 8 may be -OH and the other two instances may independently be selected from C 1-3 haloalkyl.
  • One instance of R 8 may be -OH and the other two instances may be trifluoromethyl.
  • R 7 may be ethyl in intermediate (13), intermediate of Formula VIII and the compound of Formula V, the ethyl may be substituted with 3 instances of R 8 , and one of the three instances of R 8 may be -OH.
  • R 7 may be ethyl, substituted with 3 instances of R 8 , and one of the instances of R 8 is -OH and the other two instances of R 8 may be independently selected from C 1-3 haloalkyl.
  • one instance of R 8 is -OH and the other two instances of R 8 may be trifluoromethyl.
  • Also disclosed herein is a one-step process for making a compound of Formula VI.
  • the one-step process for making a compound of Formula VI comprises coupling an appropriate amount of an amine (14) with a chloropyrimidine of Formula II, optionally in the presence of an appropriate amount of a suitable base, in a suitable aprotic organic solvent, at a suitable temperature, to yield a compound of Formula VI.
  • Also disclosed herein is another process for making a compound of Formula VI.
  • This process for making a compound of Formula VI comprises the steps of:
  • R 1 may be an unsubstituted 5-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S.
  • R 1 may be isoxazolyl.
  • R 1 may be 3-isoxazolyl.
  • R 1 may be an unsubstituted phenyl or 6-membered heteroaryl ring containing up to three ring nitrogen atoms.
  • R 1 may be phenyl.
  • R 2 may be a 6-membered heteroaryl optionally substituted with up to three instances of R 5 .
  • R 2 may be phenyl optionally substituted with up to three instances of R 5 .
  • R 2 may be phenyl substituted with one instance of R 5 .
  • R 2 may be phenyl substituted with one instance of R 5 and R 5 is halogen.
  • R 2 may be phenyl substituted with one instance of R 5 and R 5 is fluoro.
  • R 2 may be 2-fluorophenyl.
  • R 2 may be phenyl substituted with two instances of R 5 .
  • R 2 may be phenyl substituted with two instances of R 5 and each instance of R 5 is independently halogen.
  • R 2 may be phenyl substituted with two instances of R 5 and each instance of R 5 may be fluoro.
  • Compound I (1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimi din-4-yl)amino)methyl)propan-2-ol).
  • Compound I has the structure depicted below.
  • Compound I is an sGC stimulator that has demonstrated efficacy for the treatment of a number of NO related disorders in preclinical models.
  • the one-step process for making Compound I comprises coupling an appropriate amount of an amine (14) with a chloropyrimidine of Formula IV in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, at a suitable temperature, to yield Compound I.
  • An appropriate amount of amine (13) or amine (14) is at least one equivalent of amine (13) or amine (14) per each equivalent of compound of Formula II or compound of Formula IV.
  • An excess of amine (13) or amine (14) may be used.
  • An amount between about 1 and about 5 equivalents of the amine (13) or amine (14) can be used.
  • the appropriate amount may be between about 1 and about 4 equivalents. It may be between about 1 and about 3 equivalents.
  • a suitable optional base is, for instance, Hunig's base.
  • Other suitable optional bases are, for example, Et 3 N, NaHCOs, and KHCO 3 .
  • Amine (13) or amine (14) itself may also be used as the base.
  • An appropriate amount of a suitable base is at least one equivalent of optional base per each equivalent of intermediate of Formula II or intermediate of Formula IV. In some embodiments, an appropriate amount is about 2 equivalents.
  • a suitable aprotic organic solvent is dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • Other suitable aprotic organic solvents are, for instance, N,N -dimethylformamide (DMF), N,N -dimethylacetamide (DMA), and tert -butanol (t-BuOH).
  • a suitable temperature is between about 100 °C and about 135 °C.
  • a suitable temperature may be between about 120 °C and about 130 °C.
  • a suitable temperature may be between about 125 °C and about 130 °C.
  • Also disclosed is another process for making Compound I comprises the steps of:
  • An appropriate amount of ammonium hydroxide is at least 3 equivalents of ammonium hydroxide for each equivalent of intermediate (12).
  • An appropriate amount may be between about 3 equivalents and about 12 equivalents. In other embodiments, it may be between about 4 equivalents and about 10 equivalents. It may be between about 6 equivalents and about 12 equivalents. It may be between about 8 equivalents and about 10 equivalents. It may be about 10 equivalents.
  • a suitable aprotic organic solvent is, for example, a dialkyl ether.
  • the ether may be methyl t-butyl ether.
  • Other ethers that may be use include, for instance, diisopropyl ether.
  • Other aprotic organic solvents that may be used are, for example, dichloromethane and ethyl acetate.
  • a suitable temperature is between about 15 °C and about 35 °C.
  • a suitable temperature may be between about 20 °C and about 30 °C.
  • a suitable temperature may be between about 23 °C and about 28 °C.
  • an appropriate amount of an amine (14) is at least one equivalent of amine (14) per each equivalent of compound of Formula II or compound of Formula IV.
  • An excess of amine (14) may be used.
  • An amount between about 1 and about 5 equivalents of amine (14) can be used.
  • the appropriate amount may be between about 1 and about 4 equivalents. It may be between about 1 and about 3 equivalents.
  • a suitable optional base is, for instance, Hunig's base.
  • Other suitable optional bases are, for example, Et 3 N, NaHCOs, and KHCO 3 .
  • Amine (14) itself may also be used as the base.
  • An appropriate amount of a suitable base is at least one equivalent of optional base per each equivalent of intermediate of Formula II or intermediate of Formula IV.
  • An appropriate amount may be about 2 equivalents.
  • a suitable aprotic organic solvent is dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • Other suitable aprotic organic solvents are, for instance DMF, DMA, and t-BuOH.
  • a suitable temperature is between about 100 °C and about 135 °C.
  • a suitable temperature may be between about 120 °C and about 130 °C.
  • a suitable temperature may be between about 125 °C and about 130 °C.
  • An appropriate amount of amine (13) or amine (14) is at least one equivalent of amine (13) or amine (14) per each equivalent of intermediate (7) or intermediate (7').
  • An excess of amine (13) or amine (14) may be used.
  • An amount between about 1 and about 3 equivalents of the amine (13) or amine (14) can be used.
  • the appropriate amount may be between about 1 and about 2.9 equivalents. It may be between about 1 and about 2.7 equivalents. It may be about 2.6 equivalents.
  • a suitable optional base is, for instance, Hunig's base.
  • Other suitable optional bases are, for example, Et 3 N, NaHCOs, and KHCO 3 .
  • Amine (13) or amine (14) itself may also be used as the base, when used in excess.
  • An appropriate amount of a suitable base is at least one equivalent of optional base per each equivalent of intermediate (7) or intermediate (7'). An appropriate amount may be about 2 equivalents.
  • a suitable aprotic organic solvent is dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • Other suitable aprotic organic solvents are, for instance, N,N -dimethylformamide (DMF), N,N -dimethylacetamide (DMA), and tert -butanol (t-BuOH).
  • a suitable temperature is between about 50 °C and about 90 °C.
  • a suitable temperature may be between about 55 °C and about 65 °C.
  • Asuitable temperature may be between about 75 °C and about 90 °C.
  • a suitable temperature may be between about 55 °C and about 85 °C.
  • a suitable temperature may be between about 75 °C and about 85 °C.
  • a suitable temperature may be between about 50 °C and about 70 °C.
  • a suitable transfer hydrogenation reagent is HCOOH.
  • HCOOH was most commonly used in the presence of organic/inorganic bases such as Et 3 N, NaOH, NaHCO 3 , etc.
  • a suitable metal catalyst is palladium on activated carbon, for instance 10 % Pd on activated carbon.
  • An appropriate amount of a suitable metal catalyst is a catalytic amount, i.e., less than one equivalent of Pd per equivalent of intermediate of Formula VII, Formula VIII, Formula IX or Formula X. In some embodiments, an appropriate amount of the suitable metal catalyst is between 0.01 and 0.02 equivalents of Pd per equivalent of intermediate of Formula VII, Formula VIII, Formula IX or Formula X.
  • a suitable base is triethylamine (Et 3 N).
  • Other suitable bases that can be used are, for example, Hunig's base, NaHCOs, KHCO 3 , and sodium acetate.
  • An appropriate amount of a suitable base is at least one equivalent of base per each equivalent of intermediate of Formula VII, Formula VIII, Formula IX or Formula X.
  • a suitable amount of base is at least 1.5 equivalents. It may be about 1.6 equivalents.
  • a suitable temperature is between about 35 °C and about 60 °C.
  • a suitable temperature is between about 35 °C and about 55 °C.
  • a suitable temperature may be between about 40 °C and about 50 °C.
  • a suitable organic solvent is, for example, THF.
  • Other solvents that can be used are, for instance methanol, ethanol, isopropanol, 2-methyl-tetrahydrofuran or mixtures thereof.
  • the processes described herein have the advantage of allowing preparation of sGC stimulators and intermediates of Formula I in high yield and purity.
  • the present invention has the additional advantage of facile reaction conditions that are readily scaled up for large scale manufacturing.
  • the compound of Formula I is a compound of Formula II.
  • the compound of Formula I is a compound of Formula IV.
  • the compound of Formula I is a compound of Formula III.
  • it is a compound of Formula V.
  • the compound of Formula I is a compound of Formula VI.
  • the compound of Formula I is a Compound I (1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimi din-4-yl)amino)methyl)propan-2-ol).
  • intermediates (4) and (4') may be carried out in two steps.
  • the first step involves reaction of a ketone (19) with diethyloxalate to provide an intermediate (20).
  • intermediate (20) is reacted with a suitably substituted hydrazine or its corresponding hydrochloride salt.
  • the hydrazine would be one of Formula NH 2 NH-CH 2 -(2-fluorophenyl).
  • This process is advantageous over alternative processes to generate compounds of Formula III, Formula V, Formula VI and Compound I in that it uses the symmetrical intermediate (7) or (7') as the starting material.
  • This symmetrical intermediate generated from symmetrical intermediates (6) and (6'), as discussed above, results in overall high yields and purities of the subsequent steps.
  • Two high yielding steps yield the final Formula V amine.
  • the overall process is amenable to scale-up for large scale manufacturing.
  • a method or device that "comprises”, “has”, “includes” or “contains” one or more steps or elements possesses those one or more steps or elements, but is not limited to possessing only those one or more steps or elements.
  • a step of a method or an element of a device that "comprises”, “has”, “includes” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features.
  • a device or structure that is configured in a certain way is configured in at least that way, but may also be configured in ways that are not listed.
  • each range is intended to be a shorthand format for presenting information, where the range is understood to encompass each discrete point within the range as if the same were fully set forth herein.
  • Time Table Time (minute) % Solvent A % Solvent B 0 85 15 10 5 95 15 5 95 Retention Times of selected compounds: Compound Approximate Retention Time (Min) Isooxazole-3-carboxylic acid (1') 1.8 Compound (2') 3.1 Compound (3') 6.2 Compound (4') 8.6 Compound (5') 5.1 Compound (6') 6.2 Compound (7') 10.3 Compound (8') 10.0 Compound (9') 8.8 Compound (10') 7.0 Formula IV 9.3 Compound I 8.9
  • Isooxazole-3-carboxylic acid ((1'), 241.6 g, 2137 mmoles, 1.0 equiv.), toluene (1450 mL) and DMF (7.8 g, 107 mmoles, 0.05 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting slurry was heated to 45-50 °C. Oxalyl chloride (325 g, 2559 mmoles, 1.2 equiv.) was then charged via an addition funnel over the course of 2 h while maintaining the reaction temperature between 45 to 50 °C and a vigorous gas evolution was observed. A brown mixture was obtained after addition.
  • the brown mixture was heated to 87 to 92 °C over 1 h and stirred at 87 to 92 °C for 1 h.
  • the reaction was completed as shown by HPLC. During heating, the brown mixture turned into a dark solution.
  • the reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the piperidine amide by HPLC.
  • the dark mixture was cooled to 20-25 °C and then filtered through a sintered glass funnel to remove any insolubles. The dark filtrate was concentrated under reduced pressure to a volume of 400 mL dark oil.
  • the dark oil was dissolved in a solution of dichloromethane/ethyl acetate/heptane (150mL/100mL/100mL). The solution was loaded on a silica pad (410 g) and the silica pad was eluted with ethyl acetate/heptane (1/1 v/v). The filtrate ( ⁇ 3000 mL) was collected and then concentrated under reduced pressure to a volume of 150 mL to give a slurry upon standing. Heptane (200 mL) was then added to the slurry and the slurry was concentrated under reduced pressure to a volume of 150 mL.
  • Anhydrous ammonium chloride (267 g, 4991 mmoles, 5.0 equiv.) and toluene (5400 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer.
  • Trimethylaluminum in toluene (2 M, 2400 mL, 4800 mmoles, 4.8 equiv.) was charged slowly via an addition funnel while maintaining the reaction temperature at 20 to 40 °C (Note: Methane gas evolution was observed during addition). Then the mixture was heated to 75 to 80 °C over 30 min. and a clear white solution was obtained.
  • the mixture was stirred at 20 to 26 °C over 3 h after addition.
  • the mixture was allowed to separate and the bottom aqueous layer was extracted with methyl t-butyl ether (2 ⁇ 354 mL).
  • the combined organic layers were concentrated under reduced pressure to bring the volume to 303 mL.
  • Methyl t-butyl ether (354 mL) was added and the mixture was concentrated under reduced pressure to bring the volume to 303 mL.
  • Heptane (303 mL) was added and the mixture was concentrated under reduced pressure to bring the volume to 303 mL.
  • the slurry was filtered and the filter cake was washed with heptane (100 mL).
  • the organic layer was washed with a saturated sodium bicarbonate solution (1000 mL) and with 1 N HCl solution (1000 mL) and then concentrated under reduced pressure to a volume of 1500 mL.
  • the organic solution was loaded on a silica pad (800 g) and the silica pad was eluted with methyl t-butyl ether.
  • the clean fractions were collected and concentrated under reduced pressure to a volume of 2000 mL.
  • the MTBE solution was heated at 45 to 55 °C and heptane (2000 mL) was charged via an addition funnel over 30 min while maintaining the reaction temperature between 45 to 55 °C to obtain a slurry.
  • the slurry was cooled to 20 to 25 °C and stirred at 20 to 25 °C over 30 min.
  • the resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of MTBE and heptane (400 mL/600 mL).
  • the filter cake was then dried under vacuum at 45 to 55 °C over 5 hr to furnish Compound I as an off-white solid (130 g, 68% yield, >99% pure by HPLC).
  • Isooxazole-3-carboxylic acid ((1'), 3.857 kg, 34.1 moles, 1.0 equiv.), toluene (19.3 L) and DMF (0.131 L, 1.692 moles, 0.05 equiv.) were mixed in a 30 L jacketed reaction vessel equipped with nitrogen inlet-outlet, overhead stirrer, a thermocouple and an addition funnel. The resulting slurry was heated to 45 to 55 °C. Oxalyl chloride (4.8 kg, 37.8 moles, 1.11 equiv.) was then charged via an addition funnel over the course of 4 h 30 min. while maintaining the reaction temperature between 45 to 55 °C and a vigorous gas evolution was observed. A brown mixture was obtained after the addition.
  • the brown mixture was held at 45 to 55 °C for 30 min. and then heated to 85 to 95 °C and stirred at 85 to 95 °C for 1 h. During heating, the brown mixture turned into a dark mixture. The dark mixture was slowly cooled to 20 to 25 °C over the course of 4 h and the reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the disappearance of the piperidine amide by HPLC until the area /area % of (1'): piperidine amide was ⁇ 1.9). After the reaction was complete by HPLC the dark mixture was in-line filtered to 20 L rotavapor flask.
  • Toluene (3.9 L) was used to rinse the reactor and in-line filtered to 20 L rotavapor flask. The filtered reaction mixture was concentrated under reduced pressure until most toluene has been distilled to furnish 4.4 kg acyl chloride as dark oil.
  • the addition was a little exothermic and a brown mixture was obtained after the addition.
  • the reaction mixture was stirred at -10 to 0 °C for 20 min. and then warmed to 15 to 25 °C and stirred for 10 min.
  • the layers were separated and the bottom organic layer was collected and the top aqueous layer was extracted with dichloromethane (7.7 L).
  • the aqueous layer was discarded and the combined organic layers were transferred to 100 L jacketed reactor and washed with 15 wt % sodium chloride solution (11.6 L).
  • the layers were separated and the bottom organic layer was collected and the top aqueous layer was extracted with dichloromethane (3.9 L).
  • the aqueous layer was discarded and the combined organic layers were concentrated under reduced pressure until most dichloromethane was removed.
  • Tetrahydrofuran (7.7 L) was charged to this dark oil and concentrated under reduced pressure until most tetrahydrofuran was removed to furnish intermediate (2') as dark oil (4.6 kg, 86% yield, 0.01 wt% water content by KF, 98.9% pure by HPLC).
  • reaction mixture was stirred at below -55 °C for 10 min. Then 2 N HCl (10.7 L, 21.6 moles, 1.14 equiv.) was charged over 2 min. to quench the reaction while maintaining the reaction temperature below 20 °C (exotherms from -65 °C to 18 °C).
  • ethyl acetate 39 L was charged in advance to 100 L jacketed reaction vessel and the above reaction mixture from 50 L round bottom flask was quickly transferred to 100 L jacketed reaction vessel containing ethyl acetate. 20% citric acid (10.5 L, 10.93 moles, 0.57 equiv.) was charged to adjust the batch pH ⁇ 4-5 and stirred for 5 min. The bottom aqueous layer was discarded and the top ethyl acetate layer was collected and washed twice with 15 wt % sodium chloride solution (9.0 L per wash). The organic layer was in-line filtered and concentrated under reduced pressure to a volume of 9.0 L.
  • the reaction mixture was stirred at 75 to 80 °C over 21 h and a brown solution was obtained.
  • the reaction was completed by HPLC (area/area % (6'): (7') ).
  • the reaction mixture was cooled to 0 to 5 °C over 40 min. while vigorously stirring and solids precipitated out at 28 to 30°C.
  • Water (39.6 L) was charged slowly via an addition funnel over 2 h 20 min. while maintaining the reaction temperature between 0 and 10 °C.
  • the slurry was stirred at 0 to 5 °C over 30 min.
  • the resulting slurry was filtered through an 18 inch Buchner funnel.
  • the filtrate was concentrated under reduced pressure to a volume of 9.4 L to give a slurry and tetrahydrofuran was then solvent exchanged to methanol under reduced pressure via continuously feeding methanol (22.5 L).
  • the final volume after solvent exchange was 11.2 L and the tetrahydrofuran content was confirmed to be ⁇ 1 wt% by 1 H-NMR.
  • the resulting slurry was filtered through an 18 inch Buchner funnel and the filter cake was washed with methanol (3.7 L). The wet cake was dried on the filter for 25 min. and then dried under vacuum at 40 °C over 4 h until constant weight to furnish intermediate (9') as a white solid (1.54 kg, 90% yield, 98.4% pure by HPLC).
  • Ammonium hydroxide 28 to 30% solution in water, 7.7 L, 57.3 moles, 4.7 equiv.
  • methyl t-butyl ether 7.7 L
  • the condenser temp. was set to be below -10 °C and to minimize the evaporation of ammonium hydroxide).
  • the mixture was warmed to 23 to 28 °C.
  • 2,2-Bis(trifluoromethyl)oxirane ((12) , 2.2 kg, 12.22 moles, 1.0 equiv.) was charged via an addition funnel over 1 h while maintaining the reaction temperature between 20 to 30 °C.
  • the reaction mixture was stirred at 20 to 30 °C over 3 h after addition.
  • the layers were allowed to separate for 30 min. and the bottom aq. layer was extracted twice with methyl t-butyl ether (2 x 7.7 L). The aqueous layer was discarded and the combined organic layers were concentrated under reduced pressure to a volume of 6.6 L.
  • Methyl t-butyl ether (11 L) was continuously charged and concentrated to a volume of 6.6 L.
  • Methyl t-butyl ether (44 L) and water (18 L) were then charged to the reaction mixture.
  • the organic layer was washed with 1N HCl (10.6 L, 10.6 moles, 2.6 equiv.), followed by water (9.1 L).
  • the organic layer was then concentrated under reduced pressure to a volume of 13.6 L.
  • Methyl t-butyl ether (7.6 L) was charged and continued to concentrate under reduced pressure to a volume of 13.6 L.
  • the organic layer was then transferred to a 100 L reactor via in-line filtration.
  • Methyl t-butyl ether (4.5 L) was charged to the 100 L reactor via the transfer line to bring the volume to 18.1 L.
  • the MTBE solution was heated to 50 to 56 °C and heptane (18.1 L) was charged via an addition funnel over 1 h 30 min while maintaining the reaction temperature above 50 °C to obtain a slurry.
  • the resulting slurry was cooled to 15 to 25 °C and stirred at 15 to 25 °C over 30 min.
  • the slurry was filtered through an 18 inch Buchner funnel, and the filter cake was washed with a pre-mixed solution of MTBE and heptane (4.5 L/9.0 L).
  • the filter cake was dried on the filter for 1 h and then dried under vacuum at 40 °C over 4 h to furnish Compound I as an off-white solid (1.625 kg, 75% yield).
  • the resulting slurry was cooled to 40 to 50 °C over 1 hour and stirred at 40 to 50 °C over 2 hours.
  • the slurry was filtered and the solid cake was rinsed with acetonitrile/water (110 mL, 1/1 v/v) and dried under vacuum at 35 to 45 °C over 16 h to furnish the compound of Formula X as an off-white solid (27.9 g, 91% yield, 99% pure by HPLC).

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Claims (12)

  1. Procédé permettant la préparation d'un composé de formule II :
    Figure imgb0126
     dans laquelle :
    R1 représente un cycle phényle non substitué ou un cycle hétéroaryle de 5 à 6 chaînons contenant jusqu'à trois hétéroatomes cycliques indépendamment choisis parmi un atome N, O ou S;
    R2 représente un cycle phényle ou un cycle hétéroaryle de 6 chaînons, éventuellement substitué par jusqu'à trois instances de R5; ledit cycle hétéroaryle de 6 chaînons contenant jusqu'à 2 atomes cycliques d'azote ; et
    chaque groupe R5 est indépendamment choisi parmi un groupe C1-6 alkyle, C1-6 alcoxy ou un atome d'halogène ;
    ledit procédé comprenant les étapes de :
    i) amidation de la substance de départ (1)
    Figure imgb0127
    en la faisant réagir avec une quantité appropriée de chlorure d'oxalyle ou d'un réactif équivalent, dans un mélange adéquat d'eau et d'un solvant organique aprotique, à une température adéquate, en présence d'une quantité appropriée d'un catalyseur adéquat ; suivie d'une quantité appropriée de chlorhydrate de N,O-diméthylhydroxylamine, en présence d'un excès approprié d'une base adéquate, à une température adéquate, dans un mélange adéquat d'eau et d'un solvant organique aprotique pour procurer l'amide (2) ;
    Figure imgb0128
    dans lequel R1 représente un cycle phényle non substitué ou un cycle hétéroaryle de 5 à 6 chaînons contenant jusqu'à trois hétéroatomes cycliques indépendamment choisis parmi l'atome N, O ou S ;
    ii) alkylation de l'amide intermédiaire (2) avec une quantité appropriée de propiolate d'éthyle, dans un solvant organique aprotique adéquat, à une température adéquate, en présence d'une quantité appropriée d'une base adéquate, pour procurer le β-énaminocétoester (3) ;
    Figure imgb0129
    iii) condensation du β-énaminocétoester (3) avec une quantité appropriée d'hydrazine de formule R2-CH2-NH-NH2 ou de son sel de HCl, éventuellement en présence d'une quantité appropriée d'une base adéquate, dans un solvant protique adéquat, à une température adéquate, qui procure l'intermédiaire d'ester de pyrazole (4)
    Figure imgb0130
     dans lequel R2 représente un cycle phényle ou un cycle hétéroaryle de 6 chaînons, tous deux éventuellement substitués par jusqu'à trois instances de R5 ; ledit cycle hétéroaryle de 6 chaînons contenant jusqu' à 2 atomes cycliques d'azote ;
    iv) amination de l'intermédiaire d'ester de pyrazole (4) avec une quantité appropriée de chlorure d'ammonium, en présence d'une quantité appropriée de triméthylaluminium, dans un solvant organique aprotique adéquat, à une température adéquate, qui procure l'amidine (5A), ou, après traitement avec un acide minéral aqueux adéquat, le sel d'amidine (5B) :
    Figure imgb0131
    v) condensation de l'amidine (5A) ou du sel d'amidine (5B) et d'une quantité appropriée de fluoromalonate, éventuellement en présence d'une quantité appropriée d'une base adéquate, dans un solvant protique adéquat, à une température adéquate pour procurer, après traitement avec une quantité appropriée d'un acide minéral adéquat, le diol (6)
    Figure imgb0132
    vi) chloration du diol (6) avec une quantité appropriée de chlorure de phosphoryle, à une température adéquate, dans un solvant organique aprotique adéquat, éventuellement en présence d'une quantité appropriée d'une base adéquate, pour procurer la dichloropyrimidine (7)
    Figure imgb0133
    vii) mono-méthoxylation de la dichloropyrimidine (7) avec une quantité appropriée de méthoxyde de sodium, à une température adéquate, dans un solvant protique approprié, pour procurer la méthoxypyrimidine (8)
    Figure imgb0134
    viii) dé-chloration de la méthoxypyrimidine (8) avec de l'hydrogène gazeux ou un réactif d'hydrogénation par transfert et, éventuellement, une quantité appropriée d'un catalyseur métallique adéquat, en présence d'une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique approprié, pour produire la fluorométhoxypyrimidine (9)
    Figure imgb0135
    ix) dé-méthylation de la fluorométhoxypyrimidine (9) en la faisant réagir avec une quantité appropriée d'un acide aqueux dans un solvant protique approprié, à une température adéquate, pour procurer l'alcool (10)
    Figure imgb0136
     et
    x) chloration de l'alcool (10) avec une quantité appropriée de chlorure de phosphoryle et éventuellement une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique aprotique adéquat.
  2. Procédé permettant la préparation d'un composé de formule II :
    Figure imgb0137
     dans laquelle :
    R1 représente un cycle phényle non substitué ou un cycle hétéroaryle de 5 à 6 chaînons contenant jusqu'à trois hétéroatomes cycliques indépendamment choisis parmi l'atome N, O ou S;
    R2 représente un cycle phényle ou un cycle hétéroaryle de 6 chaînons, tous deux éventuellement substitués par jusqu'à trois instances de R5 ; ledit cycle hétéroaryle de 6 chaînons contenant jusqu'à 2 atomes cycliques d'azote ; et
    chaque R5 est indépendamment choisi parmi un groupe C1-6 alkyle, C1-6 alcoxy ou un atome d'halogène ;
    ledit procédé comprenant les étapes de :
    1) mono-hydroxylation d'une dichloropyrimidine (7)
    Figure imgb0138
     avec une quantité appropriée d'hydroxyde de sodium, à une température adéquate, dans un mélange adéquat d'un solvant aprotique et d'un solvant protique, en présence d'une quantité appropriée d'un catalyseur de transfert de phase adéquat, pour procurer l'hydroxypyrimidine (8B) ;
    Figure imgb0139
    2) dé-chloration de l'hydroxypyrimidine (8B) avec de l'hydrogène gazeux ou un réactif d'hydrogénation par transfert et, éventuellement, une quantité appropriée d'un catalyseur métallique adéquat, en présence d'une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique adéquat, pour fournir la fluorohydroxypyrimidine (10) ;
    Figure imgb0140
     et
    3) chloration de l'alcool de fluorohydroxypyrimidine (10) avec une quantité appropriée de chlorure de phosphoryle et éventuellement une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique aprotique adéquat.
  3. Procédé selon la revendication 1 permettant la préparation d'un composé de formule IV
    Figure imgb0141
     ledit procédé comprenant les étapes de :
    i) amidation de la substance de départ (1')
    Figure imgb0142
     en la faisant réagir avec une quantité appropriée de chlorure d'oxalyle ou d'un réactif équivalent, dans un solvant organique aprotique adéquat, à une température adéquate, en présence d'une quantité appropriée d'un catalyseur adéquat ; suivie d'une quantité appropriée de chlorhydrate de N,O-diméthylhydroxylamine, en présence d'un excès approprié d'une base adéquate, à une température adéquate, dans un mélange adéquat d'eau et d'un solvant organique aprotique pour procurer l'amide (2')
    Figure imgb0143
    ii) alkylation de l'amide intermédiaire (2') avec une quantité appropriée de propiolate d'éthyle, dans un solvant organique aprotique adéquat, à une température adéquate, en présence d'une quantité appropriée d'une base adéquate, pour procurer le β-énaminocétoester (3')
    Figure imgb0144
    iii) condensation du β-énaminocétoester (3') avec une quantité appropriée d'une hydrazine de formule NH2NH-CH2-(2-fluorophényle) ou de son sel de HCl, éventuellement en présence d'une quantité appropriée d'une base adéquate, dans un solvant protique adéquat, à une température adéquate, qui procure l'intermédiaire d'ester de pyrazole (4')
    Figure imgb0145
    iv) amination de l'intermédiaire d'ester de pyrazole (4') avec une quantité appropriée de chlorure d'ammonium, en présence d'une quantité appropriée de triméthylaluminium, dans un solvant organique aprotique adéquat, à une température adéquate, qui procure l'amidine (5'A), ou, après traitement avec un acide minéral aqueux adéquat, le sel d'amidine (5'B) ;
    Figure imgb0146
    v) condensation de l'amidine (5'A) ou du sel d'amidine (5'B) et d'une quantité appropriée de fluoromalonate, éventuellement en présence d'une quantité appropriée d'une base adéquate, dans un solvant protique adéquat, à une température adéquate pour procurer, après traitement avec une quantité appropriée d'un acide minéral adéquat, le diol (6') ;
    Figure imgb0147
    vi) chloration du diol (6') avec une quantité appropriée de chlorure de phosphoryle, à une température adéquate, dans un solvant organique aprotique adéquat, éventuellement en présence d'une quantité appropriée d'une base adéquate, pour procurer la dichloropyrimidine (7') ;
    Figure imgb0148
    vii) mono-méthoxylation de la dichloropyrimidine (7') avec une quantité appropriée de méthoxyde de sodium, à une température adéquate, dans un solvant protique approprié, pour procurer la méthoxypyrimidine (8') ;
    Figure imgb0149
    viii) dé-chloration de la méthoxypyrimidine (8') avec de l'hydrogène gazeux ou un réactif d'hydrogénation par transfert et, éventuellement, une quantité appropriée d'un catalyseur métallique adéquat, en présence d'une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique approprié, pour produire la fluorométhoxypyrimidine (9') ;
    Figure imgb0150
    xi) dé-méthylation de la fluorométhoxypyrimidine (9') en la faisant réagir avec une quantité appropriée d'un acide aqueux, dans un solvant protique approprié, à une température adéquate, pour procurer l'alcool (10') ;
    Figure imgb0151
     et
    x) chloration de l'alcool (10') avec une quantité appropriée de chlorure de phosphoryle et, éventuellement, une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique aprotique adéquat.
  4. Procédé selon la revendication 2, permettant la préparation d'un composé de formule IV
    Figure imgb0152
     ledit procédé comprenant les étapes de
    1) mono-hydroxylation d'une dichloropyrimidine (7')
    Figure imgb0153
     avec une quantité appropriée d'hydroxyde de sodium, à une température adéquate, dans un mélange adéquat d'un solvant aprotique et d'un solvant protique, en présence d'une quantité appropriée d'un catalyseur de transfert de phase adéquat, pour procurer l'hydroxypyrimidine (8'B) ;
    Figure imgb0154
    2) dé-chloration de l'hydroxypyrimidine (8'B) avec de l'hydrogène gazeux et un réactif d'hydrogénation par transfert et, éventuellement, une quantité appropriée d'un catalyseur métallique adéquat, en présence d'une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique adéquat, pour produire la fluorohydroxypyrimidine (10') ;
    Figure imgb0155
     et
    3) chloration de l'alcool (10') avec une quantité appropriée de chlorure de phosphoryle et éventuellement une quantité appropriée d'une base adéquate, à une température adéquate, dans un solvant organique aprotique adéquat.
  5. Procédé selon la revendication 1 ou 2, R1 représentant un cycle hétéroaryle de 5 chaînons contenant jusqu'à trois hétéroatomes indépendamment choisis parmi l'atome N, O ou S.
  6. Procédé selon la revendication 5, R1 représentant un groupe isoxazolyle.
  7. Procédé selon la revendication 5, R1 représentant un groupe 3-isoxazolyle.
  8. Procédé selon la revendication 1 ou 2, R2 représentant un cycle phényle éventuellement substitué par jusqu'à trois instances de R5.
  9. Procédé selon la revendication 8, R2 représentant un cycle phényle substitué par une instance de R5, R5 représentant un atome d'halogène.
  10. Procédé selon la revendication 9, R5 représentant un groupe fluoro.
  11. Procédé selon la revendication 8, R2 représentant un cycle phényle substitué par deux instances de R5 ; chaque instance de R5 étant indépendamment choisie parmi un atome d'halogène.
  12. Procédé selon la revendication 11, chaque instance de R5 représentant un groupe fluoro.
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AU2017291827B2 (en) 2021-10-21
US11773089B2 (en) 2023-10-03
KR102487872B1 (ko) 2023-01-12
ES2963563T3 (es) 2024-03-27
MA45603A (fr) 2019-05-15
CA3029375A1 (fr) 2018-01-11
EP4249488A2 (fr) 2023-09-27
IL263995A (en) 2019-02-28
SG11201900096QA (en) 2019-02-27
MX2022001495A (es) 2022-03-11
JP7112384B2 (ja) 2022-08-03
US20210323951A1 (en) 2021-10-21
US20220227748A1 (en) 2022-07-21
MX2019000105A (es) 2019-04-22
EP4249488A3 (fr) 2023-12-20
EP3481818A1 (fr) 2019-05-15
AU2017291827A1 (en) 2019-02-07
CL2019000016A1 (es) 2019-05-03
WO2018009597A1 (fr) 2018-01-11
IL263995B (en) 2021-02-28
BR112019000291A2 (pt) 2019-04-16
JP2019525913A (ja) 2019-09-12
US20240059684A1 (en) 2024-02-22
EP3481818C0 (fr) 2023-09-06
CL2023000228A1 (es) 2023-09-29
CN109563077A (zh) 2019-04-02
KR20190025986A (ko) 2019-03-12
EA201990237A1 (ru) 2019-08-30

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